Lipoprotein(a) and cardiovascular disease.

Elevated plasma levels of lipoprotein(a) (Lp(a)) are a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease. Lp(a) consists of a lipoprotein particle resembling low density lipoprotein and the covalently-attached glycoprotein apolipoprotein(a) (apo(a)). Novel therapeutics that specifically and potently lower Lp(a) levels are currently in advanced stages of clinical development, including in large, phase 3 cardiovascular outcomes trials. However, fundamental unanswered questions remain concerning some key aspects of Lp(a) biosynthesis and catabolism as well as the true pathogenic mechanisms of the particle. In this review, we describe the salient biochemical features of Lp(a) and apo(a) and how they underlie the disease-causing potential of Lp(a), the factors that determine plasma Lp(a) concentrations, and the mechanism of action of Lp(a)-lowering drugs.

Short version of the Quality of Life Relevance-Acne questionnaire.

INTRODUCTION: The goal of the present study was to develop a Short Version (SV) of the Quality of Life Relevance-Acne (QOLRELEVANCE-ACNE) based on the identified most relevant items for acne patients. METHODS: Members of the international internet group for acne patients were asked to fill in the short prototype version of the QOLRELEVANCE-ACNE. Internal consistency was measured using Cronbach's alpha. RESULTS: The answers of 684 acne patients were collected. The analysis revealed that the internal consistency of the instrument could be improved by removing a single item. That item was removed and the final four-item short version of the QOLRELEVANCE-ACNE-SV was formed. There is minimal or no overlapping of the QOLRELEVANCE-ACNE-SV with other brief forms of acne-specific HRQoL instruments. CONCLUSION: The four-item QOLRELEVANCE-ACNE-SV questionnaire was developed and showed good internal consistency. An international validation study of the QOLRELEVANCE-ACNE-SV will be performed.

Fibrinogen and plasma clot properties are associated with apolipoprotein B and apolipoprotein B-containing lipoproteins in Africans.

BACKGROUND: Case-control, intervention and laboratory studies have demonstrated a link between apolipoprotein B-containing lipoproteins and clot structure and thrombosis. There is, however, limited evidence on population level. OBJECTIVES: We determined the cross-sectional relationship between lipoprotein(a) (Lp(a)), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (ApoB) with fibrinogen and plasma clot properties in 1 462 Black South Africans, a population with higher fibrinogen and Lp(a) levels compared with individuals of European descent. METHODS: Data were obtained from participants in the South African arm of the Prospective Urban and Rural Epidemiology study. Clot properties analysed included lag time, slope, maximum absorbance, and clot lysis time (turbidity). Lp(a) was measured in nM using particle-enhanced immunoturbidimetry. General linear models (GLM) were used to determine the associations between ApoB and ApoB-containing lipoproteins with fibrinogen and plasma clot properties. Stepwise regression was used to determine contributors to clot properties and Lp(a) variance. RESULTS: GLM and regression results combined, indicated fibrinogen concentration and rate of clot formation (slope) had the strongest association with Lp(a); clot density associated positively with both Lp(a) and LDL-C; time to clot formation associated negatively with ApoB; and CLT demonstrated strong positive associations with both ApoB and LDL-C, while its association with Lp(a) was fibrinogen concentration dependent. CONCLUSION: These findings suggest that ApoB and the lipoproteins carrying it contribute to prothrombotic clot properties in Africans on epidemiological level and highlight potential novel prothrombotic roles for these (apo)lipoproteins to be considered for the development of targeted therapeutic approaches to address thrombotic conditions related to clot properties.

What's next for lipoprotein(a)? A national lipid association report from an expert panel discussion.

This is an exciting time in the lipoprotein(a) (Lp(a)) field. Attention to this important lipoprotein and potent cardiovascular risk marker is transitioning from the purview of the specialist to that of the general practitioner. Its clinical adoption as an important test is increasing in momentum. There is evidence that Lp(a) contributes to the pathology of atherothrombotic disease, aortic valve stenosis, and childhood ischemic strokes. Three large, Phase 3, randomized, cardiovascular outcomes trials in which Lp(a) is specifically and substantially lowered by mRNA-directed therapies in secondary prevention settings are in progress and will start to report results as early as 2025. Regardless of outcomes, there remain many unanswered questions about Lp(a), ranging from fundamental unknowns about Lp(a) biology, to the complexity of its measurement, optimal screening strategies, and clinical management in individuals with high Lp(a) levels both with and without overt cardiovascular disease. Accordingly, The National Lipid Association (NLA) convened an Expert Discussion involving clinicians and fundamental researchers to identify knowledge gaps in our understanding of Lp(a) biology and pathogenicity and to discuss approaches in the management of elevated Lp(a) in different clinical settings. (183 words).

Topical treatment of pyoderma gangrenosum: A systematic review.

Systemic immunosuppressants are the mainstay of treatment for pyoderma gangrenosum (PG), but they generally have significant side effects which may be avoided by limiting treatment to topical therapy. This review aimed to assess the efficacy and safety of topical treatments for PG. An extensive literature search identified nineteen suitable publications for analysis, including two open cohort studies, five case series and twelve single case reports. The quality of evidence in the publications was graded and data relating to topical PG treatment was extracted. The lack of randomised clinical trials investigating topical monotherapy for PG means that robust statistical analysis was not possible. The greatest weight of the current evidence for topical therapy favours either corticosteroids or calcineurin inhibitors. According to our review, both these options appear well tolerated with a few side effects and may have similar efficacy in speeding up the resolution of PG ulcers. Topical therapy could be considered for use in combination with systemic treatment. There may also be a role for isolated topical monotherapy in selected patients with PG, especially those with early or mild disease and those with idiopathic PG. However further research is needed to confirm this and establish optimal treatment approaches for this condition.

Identification of heparin interaction sites on thrombin-activatable fibrinolysis inhibitor that modulate plasmin-mediated activation, thermal stability, and antifibrinolytic potential.

Background: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen that provides a molecular link between coagulation and fibrinolysis. Studies have shown that the presence of glycosaminoglycans accelerates TAFI activation by plasmin and stabilizes activated TAFI (TAFIa). Objectives: We aimed to define the elements of TAFI structure that allow these effects. Methods: Based on crystallographic studies and homology to heparin-binding proteins, we performed mutagenesis of surface-exposed charged residues on TAFI that putatively constitute heparin-binding sites. We determined heparin binding, kinetics of activation by plasmin in the presence or absence of heparin, thermal stability, and antifibrinolytic potential of each variant. Results: Mutagenesis of Lys211 and Lys212 did not impair heparin binding but affected the ability of TAFI to be activated by plasmin. Mutagenesis of Lys306 and His308 did not impair heparin binding, but mutation of His308 had a severe negative effect on TAFI/TAFIa function. Mutation of Arg320 and Lys324 in combination markedly decreased heparin binding but had no effect on heparin-mediated acceleration of TAFI activation by plasmin while somewhat decreasing TAFIa stabilization by heparin. Mutagenesis of Lys327 and Arg330 decreased (but did not eliminate) heparin binding while decreasing the ability of heparin to accelerate plasmin-mediated TAFI activation, stabilize TAFIa, and increase the antifibrinolytic ability of TAFIa. A quadruple mutant of Arg320, Lys324, Lys327, and Arg330 completely lost heparin-binding ability and stabilization of the enzyme by heparin. Conclusion: Basic residues in the dynamic flap of TAFIa define a functionally relevant heparin-binding site, but additional heparin-binding sites may be present on TAFI.

Development of the acne-specific quality of life questionnaire Quality of Life Relevance-Acne.

Background: Participating members of the European Academy of Dermatology and Venereology Task Forces on quality of life (QoL) and Patient Oriented Outcomes and Acne, Rosacea and Hidradenitis Suppurativa initiated data collection in 9 European countries and formed the list of the most relevant topics for acne patients. Objective: The aim of this study was to develop a new acne-specific health-related QoL instrument based on the list of the most relevant topics for acne patients. Methods: After assessment by acne patients (n = 715) on how clear and relevant the items in the prototype questionnaire were, a group of experts on acne and QoL performed discussions on items inclusion, which resulted in a series of 21 items. Then another group of acne patients (n = 1502) filled in the new version of the instrument. A factor analysis was conducted on the 21-item version. Results: Three-factor model with 19 items indicated a satisfactory fit. The three dimensions were called: Socioemotional; Symptoms; Stigma and Suicidal thoughts. Limitations: Included patients and experts may not fully represent acne patients and health care professionals worldwide. Conclusion: A final 19-item version of the Quality of Life Relevance-Acne was developed.

Burden of atopic dermatitis in Europe: A population-centred approach leveraging web search data in 21 European countries.

BACKGROUND: The complexity, high prevalence, and substantial personal and socioeconomic burden collectively render atopic dermatitis (AD) a major public health concern. Using crowdsourced Internet data has the potential to provide unique insights into this concern, as demonstrated by several previous studies. However, a comprehensive comparison across European countries remains lacking. OBJECTIVES: The study aimed to investigate AD-related web searches across Europe to assess spatiotemporal variations and associations between disease-related and external factors. METHODS: AD-related web search data were extracted for 21 European countries between February 2019 and January 2023. Descriptive analysis and autocorrelation functions were performed to examine spatiotemporal patterns. Correlations (r) were used to evaluate the associations between web searches and disease-related, socioeconomic and meteorological data. RESULTS: Over 241 million AD-related web searches were identified, with search volume varying substantially among European countries (p < 0.001) and correlating with AD prevalence and disease burden (both r = 0.51, p = 0.019). Search volume increased between 2019 and 2023 in all countries and seasonally peaked in January and March. Negative correlations with median population age (r = -0.46, p = 0.039), number of general practitioners (r = -0.29, p = 0.226) and specialists (r = -0.27, p = 0.270) were observed. Moderate to strong correlations were found between search volume and cold, humid and windy weather with fewer sunshine hours, while higher online interest typically occurred 1-3 months after such weather conditions. CONCLUSION: The study highlights the great potential of online crowdsourced data analysis, for example, to investigate the impact of climate change or to identify unmet needs at a population level. Furthermore, the growing online interest in AD and the corresponding seasonal peaks emphasize the necessity of adapting treatment plans, intensifying public health campaigns, and disseminating reliable online information by governments and healthcare providers, especially during these periods.

A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice.

Since the 2019 National Lipid Association (NLA) Scientific Statement on Use of Lipoprotein(a) in Clinical Practice was issued, accumulating epidemiological data have clarified the relationship between lipoprotein(a) [Lp(a)] level and cardiovascular disease risk and risk reduction. Therefore, the NLA developed this focused update to guide clinicians in applying this emerging evidence in clinical practice. We now have sufficient evidence to support the recommendation to measure Lp(a) levels at least once in every adult for risk stratification. Individuals with Lp(a) levels <75 nmol/L (30 mg/dL) are considered low risk, individuals with Lp(a) levels ≥125 nmol/L (50 mg/dL) are considered high risk, and individuals with Lp(a) levels between 75 and 125 nmol/L (30-50 mg/dL) are at intermediate risk. Cascade screening of first-degree relatives of patients with elevated Lp(a) can identify additional individuals at risk who require intervention. Patients with elevated Lp(a) should receive early, more-intensive risk factor management, including lifestyle modification and lipid-lowering drug therapy in high-risk individuals, primarily to reduce low-density lipoprotein cholesterol (LDL-C) levels. The U.S. Food and Drug Administration approved an indication for lipoprotein apheresis (which reduces both Lp(a) and LDL-C) in high-risk patients with familial hypercholesterolemia and documented coronary or peripheral artery disease whose Lp(a) level remains ≥60 mg/dL [∼150 nmol/L)] and LDL-C ≥ 100 mg/dL on maximally tolerated lipid-lowering therapy. Although Lp(a) is an established independent causal risk factor for cardiovascular disease, and despite the high prevalence of Lp(a) elevation (∼1 of 5 individuals), measurement rates are low, warranting improved screening strategies for cardiovascular disease prevention.

Optimization of plasma-based BioID identifies plasminogen as a ligand of ADAMTS13.

ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13, regulates the length of Von Willebrand factor (VWF) multimers and their platelet-binding activity. ADAMTS13 is constitutively secreted as an active protease and is not inhibited by circulating protease inhibitors. Therefore, the mechanisms that regulate ADAMTS13 protease activity are unknown. We performed an unbiased proteomics screen to identify ligands of ADAMTS13 by optimizing the application of BioID to plasma. Plasma BioID identified 5 plasma proteins significantly labeled by the ADAMTS13-birA* fusion, including VWF and plasminogen. Glu-plasminogen, Lys-plasminogen, mini-plasminogen, and apo(a) bound ADAMTS13 with high affinity, whereas micro-plasminogen did not. None of the plasminogen variants or apo(a) bound to a C-terminal truncation variant of ADAMTS13 (MDTCS). The binding of plasminogen to ADAMTS13 was attenuated by tranexamic acid or ε-aminocaproic acid, and tranexamic acid protected ADAMTS13 from plasmin degradation. These data demonstrate that plasminogen is an important ligand of ADAMTS13 in plasma by binding to the C-terminus of ADAMTS13. Plasmin proteolytically degrades ADAMTS13 in a lysine-dependent manner, which may contribute to its regulation. Adapting BioID to identify protein-interaction networks in plasma provides a powerful new tool to study protease regulation in the cardiovascular system.

Optimal Dosing of Levetiracetam for Seizure Prophylaxis in Critically Ill Patients: A Prospective Observational Study.

OBJECTIVES: Critically ill patients eliminate levetiracetam (LEV) more rapidly than healthy controls, yet low doses are commonly used for seizure prophylaxis in the ICU setting. We compared the rates of achievement of target serum levels and new onset seizure (clinical and/or electrographic) among patients who received low (500 mg bid) versus high (750-1,000 mg bid) dose LEV. DESIGN: Prospective, observational study. SETTING: Tertiary care, academic center. PATIENTS: We included patients who received prophylactic LEV following traumatic brain injury, intracerebral hemorrhage, spontaneous subarachnoid hemorrhage, or supratentorial neurosurgery between 2019 and 2021. Patients with a history of seizure, antiseizure medication use, or renal failure requiring dialysis were excluded. INTERVENTIONS: None. MEASUREMENTS: LEV levels were obtained at steady state. The impact of low-dose versus high-dose LEV on the primary outcome of target LEV levels (12-46 µg/mL), and the secondary outcome of clinical and/or electrographic seizure, were assessed using multivariable logistic regression analyses adjusting for age, LEV loading dose, BMI, primary diagnosis and creatinine clearance (CrCl). MAIN RESULTS: Of the 205 subjects included in analyses, n = 106 (52%) received LEV 500 mg bid (median 13 mg/kg/d), and n = 99 (48%) received LEV 750-1,000 mg bid (median 25 mg/kg/d). Overall, 111 of 205 patients (54%) achieved target levels: 48 (45%) from the low-dose group versus 63 (64%) from the high-dose group (odds ratio [OR] 2.1; 95% CI, 1.1-3.7; p = 0.009). In multivariable analyses, high-dose LEV predicted target levels (adjusted OR [aOR] 2.23; 95% CI, 1.16-4.27; p = 0.016), and was associated with lower seizure odds (aOR 0.32; 95% CI, 0.13-0.82; p = 0.018) after adjusting for age, loading dose, BMI, diagnosis, and CrCl. CONCLUSIONS: Underdosing of LEV was common, with only 54% of patients achieving target serum levels. Higher doses (750-1,000 mg bid) were more than twice as likely to lead to optimal drug levels and reduced the odds of seizure by 68% compared with low-dose regimens (500 mg bid).

Scleroderma Secondary to Pembrolizumab: A Case Report and Review of 19 Cases of Anti-PD-1-Induced Scleroderma.

Immune checkpoint inhibitors are increasingly being used to treat various malignancies. Despite their efficacy, they are known to potentially cause immune-related adverse effects, including dermatological manifestations. A rare cutaneous immune-related adverse effect is scleroderma, which has been reported to occur with anti-programmed cell death-1 (PD-1) agents such as pembrolizumab and nivolumab. This may present with skin tightening and hardening at any point during or after immunotherapy. We present the case of a 54-year-old Caucasian woman who, following 16 doses of pembrolizumab for breast cancer, developed clinical features of scleroderma confirmed on histology. She was initially treated with oral corticosteroids, followed by oral psoralen-UVA, with poor response, but eventually improved with methotrexate. A literature review revealed 12 other cases of scleroderma following pembrolizumab treatment and 6 cases of scleroderma following nivolumab treatment. Males and females were both affected, and their ages ranged from 33 to 81 years. Scleroderma developed at different stages of pembrolizumab or nivolumab therapy. Although scleroderma is not commonly drug-induced, anti-PD-1 agents may be a rare cause and it is important to elicit an accurate drug history, including immunotherapy, in such cases.

Responsiveness and Minimal Clinically Important Difference of the Infants and Toddlers Dermatology Quality of Life Questionnaire.

BACKGROUND: The Infants and Toddlers Dermatology Quality of Life (InToDermQoL) is the dermatology-specific proxy health-related quality of life (HRQoL) instrument for children from birth to 4 years. The aim of the present study was to confirm the responsiveness and establish minimal clinically important difference (MCID) for the InToDermQoL. METHODS: Parents of children with skin diseases were asked to fill in the InToDermQoL at the initial visit (T1) and subsequent consultation (T2). We hypothesized that correlations between change scores of the InToDermQoL and change scores of global assessment of clinical severity by dermatologists and by patients' parents should be above 0.3. The receiver operating characteristic (ROC) curves method was also used for confirmation of responsiveness and determination of MCIDs of the InToDermQoL. The area under the ROC curve (AUC) was used as an indicator of responsiveness. RESULTS: Results of 442 patients were included. Correlations between change scores of age-specific versions of the InToDermQoL and change scores of global assessment of clinical severity by dermatologists and by patients' parents were above 0.3 (0.46-0.74). AUCs for age-specific versions of the InToDermQoL were acceptable (above 0.7) or excellent (above 0.8). Estimated MCIDs for the InToDermQoL were as follows: 3 points of total score change for 0-11 months, 5 for 1-2 years and 3 or 4 for 3-4 years version. Estimated MCIDs for the InToDermQoL version for 1-2-year-old children was higher than MCIDs for the 3-4-year-old version despite the higher number of items in the latter. Therefore a MCID of 5 was recommended for both these versions. CONCLUSIONS: Responsiveness for all age-specific versions of the InToDermQoL questionnaire was confirmed. MCIDs for the InToDermQoL are proposed as follows: 3-point change of the total score for age version 0-11 months and 5-point for the age versions 1-2 years and 3-4 years.

Impact of asthma in Europe: A comparison of web search data in 21 European countries.

Background: Asthma is a chronic inflammatory disorder of the airways and one of the most important non-communicable diseases worldwide. Analyzing crowdsourced data can help understand public interest and unmet needs as well as potential factors influencing search behavior. Objective: The study aimed to investigate asthma-related web search data in Europe to identify possible regional and seasonal variations and to assess public interest. Methods: Google Ads Keyword Planner was used to measure search volume for search terms related to asthma, allergic asthma, and bronchial asthma in 21 European countries between January 2018 and December 2021. The top 10 keywords of each country were categorized qualitatively. Search volume per 100 000 inhabitants was descriptively assessed in terms of regional and seasonal trends. Spearman correlations between search volume and pollen concentration as well as coronavirus disease (COVID-19) cases were investigated. Results: The median search volume per 100 000 inhabitants for asthma and allergic asthma was highest in Northern and Western Europe, while the highest search volume for bronchial asthma was observed in Western and Eastern regions. A seasonal trend was identified for all search terms and in all regions. Correlations were found between search frequency and pollen load and search behavior and COVID-19 cases. Overall, Europeans were most interested in the diseases in general, their treatment options, and symptoms. Conclusion: These results highlighted the need for reliable and region-specific information about the disease and for public campaigns to improve asthma control. The study also emphasizes the importance of using crowdsourced data for a more encompassing overview beyond conventional healthcare data.